Interesting aspects of Herpetic Infections

No infection is as intriguing as the Herpetic infection.  Its interest lays in several facts
1. The mere fact that a Third of the US population may be involved makes this disease one of the most prevalent ones,  but it is also feared.  Whether the fear is justified or not remains a question.
2. Certainly it has something to do with horrific stories of potential recurrence of horrific burning neuropathic pains that we have heard about. Science does not know for sure whether only specific viral serotypes lead to this or whether certain hosts genes isoforms or inflammatory reactions  may be contributing to this presentation.
3. The outbreak is accompanied with guilt and sense of guiltiness that is mostly unjustified...many questions arise after the realization that those painful skin or otherwise lesions could be herpetic...that a partner you have gave this to you and that you may give this to a new partner?  Those questions are valid but with the prominence of the prevalence of this disease in the US, who and when one got exposed to Herpes is one of the great mysteries in herpetic disease.  Herpes 1 has been linked to Over crowding, and Herpes 2 is the one with a sexual connotation.  But one should remember that the Herpetic Virus will invade teguments (particularly abrasions) when contact happens, sexual or not!  And very often this happens in our tender ages of infancy.  Remember the infection can be symptomatic, but most of the time completely without any clinical manifestations. And enters quietly a dormancy.
4. The dormancy itself is quite a puzzling event!  All we know is that the capsule to this double stranded DNA viral particule is from the host!  This may help it to be "tolerated " by the host.  We can speculate that class I MHC will not be bothered. Only the class II may note the invader most likely and provide the Antibody that we can measure!
5. The exacerbation of the herpetic infection is also puzzling in many ways
-It happens when we are under stress (menstruation and exposure to UV light), pregnancy state and post chemotherapy, the so called state of "when the immune system" is down!
-To the writer this is a state of activity of the c-JUN and Fos, the NF-kB and full epigenetic phenomena as if cyclines and TNF, TGFs are in full swing!  Epigenetic events seem to free or unleash genes (regulators or not) that will reactivate the Virus.
-How and where these events occur (Golgi, Nucleus, or cytosolic) remains to be clarified.

 (Let raise the eyelid of this dormant disease and look at it through its eyes/pupils without awakening it!)

6. The bad exacerbation could be virally induced or it could be in fact a reaction of the Host  (Neutrophilic Grazymes) or Cyclin effects.  ie. In post Brain trauma injury (TBI) we know that post synaptic nerve death is due to  Cytokins that kill post synaptic nerve, is it the same in this herpetic disease?And if it is, what would be the therapeutic implications?!

Esophageal Cancer (continued)

We have discussed that chemical, traumatic and sometimes burns from caustic solutions that people ingest unfortunately, that will stimulate the cellular membrane receptors which in turn will stimulate RAS, which in turn will amplify PI3K, MAP Kinase and RAL/CDC42.   But remember these are stressful stimulations, so instead of the standard MAPK, the stimulation is imposing on RAS to awake the NFkB pathway, the c_JUN and at nuclear level the FOS which results in inflammatory proteins stimulation including cyclin production or liberation from membranes with extracellular release of Metalloproteases. Cyclins combining to CDCs will exacerbate cell divisions and proliferation, growth factors will promote cell growth, there is an associated ligase proliferation that will impact P53 (through MDM2) and  c-MYC, NOTCH, and even c_JUN itself through FBW7/hCDC4.  This is how the proteasomes come into play!

By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7.  Oh! also find MYCN and the p isoform to q for answers!)

2 Rb1 does sequester E2F.   you can look at it both ways.  that E2F stabilize Rb1 instead,  whichever way one stop the other for acting!   Remember E2F activates CPP32 which increase APOPTOSIS!  (DRUM UP THOSE TARGET THERAPY!)

3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL!  ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED.  BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS!  MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!

4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected?   Will it increase the right Ligand (FBW7)?

CELLULAR LANGUAGE (II)

In Cellular Language I published recently that we tried to emphasize that big functions of the cell start up with an on-and-off switch.  The Tic and The Tan like in MORSE language, the 1and 0 of the computer.  While this is true, there are many other simple things at the molecular level that are just as simple, but full of physiologic and scientific implications.

1.ON and OFF switch:
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 Events that lead to cancer are sometimes an exaggeration of a signal.  The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously.  Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress),  MYC (the dangerous  leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember) 

Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer. 
Therefore, a simple switch can kill you with one of the most devastating diseases.

2. Change of shape:
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To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).

At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'.  They basically cross the thickness of the cellular membrane and,  outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it!  Only division of DNA, this, they don't do.  But the membrane has to be divided also to make 2 cells in cell divison.   Even anti-coagulation happens here.  The versatility of the integrins is linked to the variety of subunits it is composed with.  Some are nature of cell specific and some are contact specific.  By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).

Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed.  If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out.  This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.

That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific.  Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.

CELL ADHESION- "join at the hip"
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At many points the cells are joined to each other at the hips of the Talins.  Say,  at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign.  These 2 integrins will be attached, and cell adhesion is achieved.  Simple as that!

Wheels of cellular migration,
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Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground.  The cell is that smart at the membrane.

More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...